6.19-amino androstanes



Uite

3,67%331 dfi-AMENG ANDRGSTANES Albert Bowers, Mexico City, Mexico, nsstgnor, by mesne gss ments, to Syntax Ionic-ration, a corporation of a a No Drawing. Filed Nov. It), 1969, Ser. No. 63,373 29 Claims. (Q3. 256-4395) In the above formula R represents hydrogen or a lower alkyl group and R represents hydrogen or the acyl group of a hydrocarbon carboxylic acid of less than 12 carbon atoms which may be saturated, unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxyl, alkoxy of up to 5 carbon atoms, acyloxy of up to 8 carbon atoms, aniino, nitro or halogen. Typical ester groups are the acetate, propionate, bu tyrate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetat cyclopentylpropionate, aniinoacetate and ,B-chloropropionate.

The novel compounds of the present invention may be repared by a process illustrated by the following equation:

(3A0 Ione to Nil MO. 5 I a AC0 II i IHIOH ([DAo l I()Ac so no I $.00 AGO IV III BITE NH: 5H0

dtates Patent Ofiice Patented Feb. 2%, 1963 on I R h i i e In the above equation R and R have the same meaning as previously set forth; Ac represents the acetyl radical but other acyl radicals of hydrocarbon carboxylic acids of less than 12 carbon atoms of the type previously mena tioned may be employed.

in practicing the process outlined above, the starting compound, androstane-Efi,l7fi-di0l-6-one diacetate (i) or the Not-lower alkyl derivative thereof is prepared by reacting o -androstene-3t3,i7fi-diol diacetate or Not-lower alltyl-M-androstene-3,8,l'ifi-diol diacetate in dioxane solution containing a catalytic amount of perchloric acid with N-brornoacetamide to form 5 x-bronio-androstane-35,65, i7 3-triol-3,l7-diacctate or the 17CL-lOVlSI' alkyl derivative thereof, which upon oxidation With chromatic acid in acetone solution is converted into the corresponding 6- keto derivative. Reductivc debrornination of the latter derivative as by treatment with zinc and acetic acid affords the diacetate of androstane-3B,17/3-diol-6-one or of 17alower alkyl-androstane-3fi,l7fi-diol-6-one (I).

Upon refluxing the latter ketone with hydroxylarnine in pyridine solution, there is formed the C-6 oxime (H) which upon hydrogenation in the presence of a platinum oxide catalyst is converted into the 6-amino derivative 55 (III). The latter is then reacted with ethyl formate under anhydrous conditions to altord the (3-6 formarnide (IV) Which upon reduction with lithium aluminum hydride affords the free C-6-N-methylainino-3B-ol cornpound. Preferential esterification or" the 3-hydroxy group so is effected With acetic anhydride in pyridine and there is thus formed the 3fi-acetoxy-C-G-N-methylarnino compound (V) which upon subsequent treatment with N- chlorosuccinirnide is converted into the (l-o-N-chloro-N- methylamine (VI). Upon subjecting a sulfuric acid solution of the latter compound to ultra-violet light, there is formed the l9-chloro-6-N-1nethylarnino compound (Vii) which is treated with dilute methanolic potassium hydroxide solution for a period of time in the order of 60 hours to form the novel C-6,19-aniino-androstane-3fi,17,6- diol (VH1: R'=hydrogen) or the l7a-alky1 derivative (Villa: R'=hydrogen). Upon conventional esterification with a hydrocarbon carboxylic acid anhydride of less than 12 carbon atoms, there is formed the 3 3-monoesters of VIII and Villa and also the 3,B,l7[3-diesters of VIII. Esterification of a tertiary hydroxyl group at C-17 8 is effected by reaction with a hydrocarbon carboxylic acid anhydride in benzene solution in the presence of p-toluenesulfonic acid.

The following examples serve to illustrate but are not intended to limit the scope of the invention:

Example I A suspension of 10 g. of the diacetate of A -androstene- 35,17fi-diol in 100 cc. of dioxane was treated with 12 cc. of 0.46 N perchloric acid and then with 4 g. of N-brornoacetamide; the N-bromoacetamide was added little by little, with stirring, in the course of one hour, in the dark and maintaining the temperature around 15. The mixture was stirred for 1 hour further in the dark at room temperature; it was then decolorized by the addition of 10% aqueous sodium bisulfite solution, 1 liter of water was added and the product was extracted with methylene chloride; the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure at room temperature. The residue was crystallized from acetone-hexane to afford 3,17 diacetate, of 5a-bromo-androstanefiflfi,l7g3-triol; M.P. 172-174; [s15 44; yield 77%.

There was prepared 100 cc. of an 8 N solution of chrornic acid from 26.7 g. of chromium trioxide, 23 cc. of concentrated sulfuric acid and distilled water. A solution of 10 g. of the 3,17-diacetate of SOC-bI'OHlO-Zllldl'O- stane-3fi,6e,l7fi-triol in 100 cc. of acetone was cooled to C. and treated with the 8 N solution of chromic acid until the characteristic color of chromium trioxide persisted in the mixture. The 8 N solution of chromic acid was. added in a slow stream, under an atmosphere of nitrogen, with stirring and at 0 C. The mixture was then stirred at 0 C. under an atmosphere of nitrogen for 2 minutes further, poured into ice water and the precipitate was collected by filtration, washed with water and dried under vacuum, thus affording the diacetate of Soc-blOmO- androstane 3133,17 3 diol-6-one. A sample crystallized from acetone-hexane had M.P. 188l91; [ed -l68.

A mixture of the above compound, 10 g. of zinc dust and 250 cc. of glacial acetic acid was refluxed for 2 hours, at the end of which it was filtered through celite under an atmosphere of nitrogen and the filtrate was concentrated to a smallvolume under reduced pressure; after cooling it was diluted with ice water and the precipitate of the diacetate of androstane-3fi,17B-diol-6-one was collected by filtration, washed with water and dried.

Example II By substituting in the procedure of Example I the diacet-ate of A -androstene-3 3J7/8-diol by the diacetate of 17u-ethyl-A -androsterm-3,8,17,8-diol, there was produced the diacetate of 17 xethyl-androstane-3fi,17fi-diol-6-one.

Example III A solution of 15 g. of an-drostane-3;3,17 8-diol 6-one diacetate in 45 cc. of anhydrous pyridine was treated with 15 g. of hydroxylamine hydrochloride previously dissolved in 90 cc. of water. The mixture was refiuxed for 18 hours; it was then poured into ice water, the formed precipitate was collected by filtration, washed with water and dried. Recrystallization from methanol afforded the oxime of 3,8,17 3-diacetoxy-androstan-6-one; M.P. 253- 255 C. (9.2 g.) and a second crop, M.P. 245248 C. (2.9 g.).

Example IV A solution of 13.3 g. of the above oxime in 200 cc. of acetic acid was hydrogenated under pressure (50 pounds) overnight using 1.9 g. of platinum oxide as a catalyst. After filtration of the catalyst, the solvent was evaporated to dryness under vacuum and the residue triturated with saturated sodium bicarbonate solution, filtered and washed with water to neutral, thus yielding 6.5 g. of Git-amino- 3B,17 3-diacetoxy-androstane.

Example V 5.7 g. of 6-amino-3p,17 B-diacetoxy-androstane was refiuxed under anhydrous conditions with 120 cc. of anhydrous ethyl formate, evaporated to dryness under vacuum and the residue crystallized from acetone-hexane to afiord 35,175 diacetoxy androstane-6fl-N-formylamine; M.P. 235-238" C.;Eoz] -62(CHCl Example VI A solution of 4 g. of the above compound in 120 cc. of anhydrous tetrahydrofuran was added dropwise to a suspension of 4 g. of lithium aluminum hydride in 200 cc. of anhydrous tetrahydrofuran and the mixture was refiuxed for 1 hour with stirring. Acetone was added cautiously to decompose the excessof hydride, then saturated aqueous sodium sulfate solution and finally solid anhydrous sodium sulfate were added. The solid was filtered and washed well with hot ethyl acetate, and the filtrate and washings were evaporated to dryness under reduced pressure. and 1.1 equivalents (1 cc.) of acetic anhydride, kept at 10 for 16 hours, poured into water, heated for an additional half an hour, and the formed precipitate collected by filtration. Crystallization from acetone-hexane gave the 6 6 N-methylamino-androstane-3B,17B-diol-3-acetate compound.

Example VII Example VIII A solution of 1 g. of the chloromethylamino compound (Example VII) in 15 cc. of sulfuric acid was irradiated for 24 hours with a sun lamp; water was added and the resulting precipitate filtered to afford 6,8-N-methylamino-l9-chloro-methyl-androstatue-313,17 3-diol 3-acetatc.

Example IX 500 mg. of the final product produced in Example VIII were dissolved in 10 cc. of 1% methanolic potassium hydroxide and the mixture was kept :at room temperature for 60 hours. After dilution with water and filtration of the product, there were obtained 380 mg. of 6,l9N-methylamino-androstane-3B,17,6-diol.

Example X :By applying the procedure described in Examples III through 1X to the diacetate of 17a-ethyl-androstane- 35,17 3-diol-6-0ne prepared in Example 11, there were produced all of the compounds described in such examples having an ethyl group at C-17a.

Example XI A mixture of 500 mg. of 6,19-N-methylamino-androstane-3;8,17B-diol, 5 cc. of pyridine and 5 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water and the solid collected by filtration, washed with water and dried. There was thus obtained 6, 19-N-methylamino-androstane-3B, l7 3-diol diacetate.

Example XII By following the method of the preceding example, but using propionic, caproic and cyclopentylpropionic anhydride as esterifying agents, there were obtained the dipropionate, dicaproate and dicyclopentylpropionate ofi 6, l9-N-methylamino-androstane-3 8,175-diol.

The residue was dissolved in 15 cc. of pyridinev Example XIII Examples XI and XII were repeated, but using 170:- ethyl-6,19 N-methylamino-androstane 35,175-diol as starting material, there were thus produced 17u-ethyl- 6,1Q-N-methylamino-androstane-3fi,17 3-dio1 3-acetate and the corresponding 3-propionate, B-caproate and 3-cyclopentylpropionate.

- Example XIV By applying the method of the preceding example, but using acetic anhydride instead of propionic anhydride, 17a-ethyl-6,19-N methylamino-androstane 313,17fi-diol B-acetate and the corresponding 3-caproate were converted respectively into 17u-ethyl-6,l9-N-methylaminoandrostan 3,8,17,8-dio1- diacetate and 17a-ethyl-6,19-N- methylamino androstane-Bp,17fi-diol-3-caproate 17-acetate.

I claim:

1. A compound of the following formula:

ogo

wherein R is selected from the group consisting of hydrogen and lower alkyl and R is selected from the group consisting ofi hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 6B,l9-N-methylamino-androstane-343,1713-diol.

3. 6 3,19-N-methylamino-17a-ethylandrostane-3fl,l7fidiol.

4. The hydrocarbon carboxylic acid diesters of less 6 than 12 carbon atoms of 65,19-N-methylamino-androstane-3,8,l7;8-diol.

5. 613,19-N-methylamino-androstane-3,B,17fi-dio1 diacetate.

6. 6 8,19-N-methylamino androstane 35,17p-dio1 dipropionate.

7. The G3 hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6,8,19-N-methylamino-17a-1ower alkyl androstane-3B,1713-diol.

8. The hydrocarbon carboxylic acid diesters of less than 12 carbon atoms of 6/3,19-N-methylamino-l7a-lower alkyl-androstane-3,8,1718-dio1.

9. 17a-ethyl-6fi,19 N-methylamino androstane 3B, 17,8-diol 3-acetate.

10. 17a-ethyl-6fi,19 N-rnethylamino-androstane 3 3, 17fl-diol-3-caproate.

.1 1. 17u-ethyl-6/3,19-N-methylamino androstane 3B, 17,6-diol-3-acetate-17-propionate.

12. 17m-ethyl-6fl,1Q-N-methylamino androstane 318, l7/8-diol-diacetate.

13. 17u-ethyl-6fi,19-N-methylamino androstane 3,8, 17B-diol-3-caproate-17-acetate.

14. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6B-N-formylamino-androstane- 3;8,17fi-di0l.

15. ofl-N-formylamino androstane-3,B,l7;9-diol diacetate.

16. The C-3 hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6;.3-N-methylamino-androstane- 3/3,17 3-dio1.

17. 6/3-N-methylamino-androstane 3fi,17fl-diol 3-a-cetate. 18. The G3 hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 6B-N-chloro-N-methylaminoandrostane-3fl,17}8-diol.

19. 6 3-N-ch1oro N-methylamino-androstane 3,8,17,8- diol 3-acetate.

20. In the process of producing a 6/3,19-N-methylamino-androstane-3fi,17p3-diol the steps comprising reacting a 6-amino androstane-3,8,17B- diacylate with ethyl formate, reducing the thus formed C-6 fiormamide with lithium aluminum hydride to form 6-N-methylaminoandrostane-3 3,17fi-dio1, esterifying the latter compound and thereafter treating with a chlorinating agent N-chlorosuccinimide and then irradiating the thus formed 6/3- N chloro N methylamino androstane derivative with ultra-violet light.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,079,381 February 26 1963 Albert Bowers It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 23 to 31, the formula should appear as shown below instead of as in the patent:

column 2, lines 16 to 30 the left-hand side formula should appear as shown below instead of as in the patent:

VIII Ithydrogen Villa: R:lower alkyl Signed and sealed this 22nd day of October 1963 (Si-EAL) Ajtieiti EDWIN LI REYNOLDS :iRhEbT SWIDER Ac'tiz'zg Commissioner of Attesting Officer Patents 

1. A COMPOUND OF THE FOLLOWING FORMULA: 